Physical and computational modeling of biomolecular crowding, confinement, organization, and interactions

这一建议旨在了解发生在拥挤介质或细胞膜附近的生物分子现象。它包括如下概述的四个目标。由于其在解释染色体实验中的重要意义，在有限和拥挤的空间中研究染色体样（异质）聚合物重新引起了人们的兴趣。利用计算机模拟，我们将研究分子拥挤、约束、链交联和链非均质性如何影响这种聚合物的空间组织。这项工作将有助于确定控制染色体组织的关键参数，特别是在细菌细胞中，并通过提供解释实验的生物物理模型来推进染色体生物物理学领域。抗菌肽（AMPs）是天然存在的肽类抗生素。它们附着在细菌膜上并使其破裂。人们对利用它们作为新的抗生素很感兴趣。这种努力的一个障碍是肽与宿主细胞的相互作用，这会减少攻击细菌的肽的数量。使用生物物理模型，我们计划在生物相关介质（即宿主细胞和细菌的混合物）中表征肽参数以增强抗菌活性。我们还将研究细菌种群对抗菌肽的反应。为此，我们将在我们之前的反应模型的基础上，采用随机模拟方法来研究amp杀死细菌的反应。这个项目的结果可能会告诉我们如何克服这个障碍，帮助我们更好地理解amp是如何工作的，从而有利于我们寻找有效的amp。AMP活性的另一个决定因素是包裹革兰氏阴性菌的外膜（OMs）。脂多糖（LPS）是OM外层的关键成分，而磷脂主要定位于内层。通过扩展我们开发的生物物理模型，我们将研究amp如何与OM相互作用和渗透。这项工作将有助于澄清肽参数，以优化抗革兰氏阴性菌的活性，革兰氏阴性菌是日益严重的感染源。聚合物刷接枝膜在多种情况下是相关的，如OM的外LPS层和接枝到膜上的糖蛋白。我们计划研究聚合物刷如何改变嵌入在刷中的颗粒之间的相互作用，重点关注嵌入颗粒之间由刷引起的吸引力的可能性。本研究的结果将提供一个概念性框架，以理解观察到的整合素蛋白在癌细胞膜上聚集并将大块糖蛋白嫁接到其表面，并可能刺激对糖蛋白或其他分子成分作为治疗靶点的进一步研究。我们的建议将为受训者提供跨越物理，计算建模和生物医学应用的坚实背景。

This proposal is aimed at understanding biomolecular phenomena occurring in a crowded medium or near cell membranes. It consists of four objectives as outlined below. Because of its significance in interpreting chromosome experiments, there has been renewed interest in studying a chromosome-like (heterogeneous) polymer in a confined and crowded space. Using computer simulations, we will investigate how molecular crowding, confinement, chain cross-linking and chain heterogeneity influence the spatial organization of such a polymer. This effort will help identify the key parameters for controlling chromosome organization, especially in bacterial cells, and advance the field of chromosome biophysics by offering biophysical models for interpreting experiments. Antimicrobial peptides (AMPs) are naturally occurring peptide antibiotics. They attach to and rupture bacterial membranes. There has been much interest in utilizing them as new antibiotics. A barrier to this effort is peptide's interactions with the host cells, which diminish the number of peptides that attack bacteria. Using a biophysical model, we plan on characterising the peptide parameters for enhanced antimicrobial activity in a biologically relevant medium (i.e., a mixture of host cells and bacteria). We will also study how bacterial populations respond to AMPs. For this, we will build up on our earlier reaction model and employ a stochastic simulation approach to the reaction, by which AMPs kill bacteria. The outcome of this project will likely show how to overcome the barrier, help us understand better how AMPs work and thus benefit our endeavor in finding potent AMPs. Another determinant of AMP activity is the outer membranes (OMs) enclosing Gram-negative bacteria. Lipopolysaccharide (LPS) is a key component of the outer layer of the OM, whereas phospholipids are mainly localized to the inner layer. By extending the biophysical models we developed, we will investigate how AMPs interact with and permeabilize the OM. This effort will be useful for clarifying the peptide parameters for optimized activity against Gram-negative bacteria, which are an increasingly serious source of infection. Polymer brushes grafted membranes are relevant in a variety of contexts such as the outer LPS layer of the OM and glycoproteins grafted to membranes. We plan on studying how a polymer brush alters the interactions between particles embedded in the brush, focusing on the possibility of brush-induced attractions between the imbedded particles. The outcome of this study will offer a conceptual framework for understanding the observed clustering of integrin proteins on cancerous cell membranes with bulky glycoproteins grafted to their surfaces and likely stimulate a further investigation into the glycoproteins or other molecular components as therapeutic targets. Our proposal will offer the trainees a solid background for working across physics, computational modeling, and biomedical applications.